Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.CCCCCC.[C:28](OCC)(=[O:30])C>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:30][CH3:28])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ncc(-c2cccc(F)c2)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COc1cc(-c2cccc(F)c2)cnc1C#N
Temperature: 25 °C

Procedure:
To a 500 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser and nitrogen inlet is charged 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine, 8, (9.28 g, 40 mmol), sodium methoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, the reaction solution is heated to reflux for 20 hours. The reaction can be determined to be complete due to the disappearance of 5-(3-fluorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture is cooled to room temperature and combined with water (500 mL). The mixture is cooled to 0° C. to 5° C. and stirred for 3 hours. The resulting solid is collected by filtration and washed with water, then hexane. The resulting cake is then dried in vacuo at 40° C. to afford the desired product.
Reaction SMILES: O.[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5].[CH3:15][N:16]([CH3:18])[CH3:17]>O>[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[CH3:15][NH+:16]([CH3:18])[CH3:17].[CH3:15][NH+:16]([CH3:18])[CH3:17].[CH3:15][NH+:16]([CH3:18])[CH3:17]
Reactant: CN(C)C
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: C[NH+](C)C
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Trimethylammonium citrate solution was prepared by dissolving 1.572 g of citric acid monohydrate ACS from Sigma (Product No. C-1909) in 20 mL of water, and titrating the solution with aqueous trimethylamine to the point of equivalence. The volume was adjusted to 25 mL with water.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH3:30])[CH:5]=1.CSC.B.CO>C1COCC1>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:29])([C:25]([F:27])([F:28])[F:26])[C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:30])[CH3:32]
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(CN(C)C)c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 73.5 %

Procedure:
A solution of 7 mg (0.0153 mmol) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide (example 34) in 0.2 mL of THF was treated with 0.006 mL (0.031 mmol) of borane dimethylsulfide. The mixture was stirred at 70° C. for 10 hrs, treated with MeOH, and concentrated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 5 mg (72%) of 2-[1-(3-dimethylaminomethyl-benzyl)-2-methyl-1H-indol-5-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow oil, MS: 445 (MH+).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH3:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.Cl[C:33]1[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([N:18]([CH3:19])[C:33]3[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:20]=[CH:21][CH:22]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above-mentioned crude product of 3-(1-cyano-1-methylethyl)-N-[3-(methylamino)phenyl]benzamide in tetrahydrofuran (15 mL) were added N-ethyl-N-isopropylpropane-2-amine (345 μL, 1.98 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (314 mg, 1.50 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15→70/30), and the fractions containing the object product were concentrated under reduced pressure to give 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl](methyl)amino}-5-nitropyrimidin-4-yl thiocyanate as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:40])=[C:17]([C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: COc1c(C)c(Cc2ccc(OC(C)C)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(OC(C)C)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
An aqueous solution (5 ml) of sodium dihydrogenphosphate (1.28 g, 10.65 mmol), an aqueous solution (7 ml) of sodium chlorite (0.533 g, 6.15 mmol) and aqueous hydrogen peroxide (0.18 ml, 30%) were added to an acetonitrile solution (5 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-isopropoxybenzaldehyde (0.530 g, 1.37 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (0.475 g, 1.18 mmol, 86%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](N)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: Nc1ccc2c(c1)CNCC2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc2c(c1)CNCC2
Temperature: 120 °C

Procedure:
A solution of 1,2,3,4-tetrahydro-isoquinolin-7-amine (4.5 g, 30 mmol) in sulfuric acid (6.5 mL, 120 mmol) and water (20 mL) was cooled to 0° C. To this cold solution was added a solution of sodium nitrite (2.51 g, 36 mmol) in water (20 mL) over 15 min. After the addition, the reaction mixture was heated at 120° C. for 2 h and then allowed to cool to rt. Solid Na2CO3 was added slowly to the reaction mixture until no gas generated. A small amount of water was added to dissolve the remaining Na2CO3 and a sticky brown glue was formed. The residue was dissolved in MeOH and filtered through Celite. The filtrate was concentrated to give 1,2,3,4-tetrahydroisoquinolin-7-ol as a brown solid (3.7 g, 82% crude yield), which was directly used in the next step without further purification. MS: 150.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CCCCCC>[C:2]([N:6]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:7][C:16]([C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1)=[O:17])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)C1=CCCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)N(NC(=O)C1=CCCCC1)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (0.86 g, 0.007M) in toluene (30 ml) was added 50% sodium hydroxide (0.55 g, 0.007M). After 15 minutes, the mixture was cooled to 5° C. and cyclohexenylcarbonyl chloride (1.0 g, 0.007M) and 50% sodium hydroxide (0.55 g, 0.007M) were added separately and simultaneously so as to maintain the reaction temperature below 10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with hexane and the solid product isolated by filtration. This product (1.2 g, 0.006M) was dissolved in toluene (30 ml) and cooled on ice while stirring. To this mixture was added benzoylchloride (1.0 g, 0.007M) and 50% sodium hydroxide (1.3 g, 0.007M) simultaneously. After addition, the mixture was stirred for 1/2 hour, diluted with hexane and the solid product, N'-t-butyl-N-cyclohexenylcarbonyl-N'-benzoylhydrazine, was isolated by filtration.
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+].[CH3:42][OH:43]>ClCCCl.C(O)(=O)C>[OH:43][C:42]([C:27]([F:30])([F:29])[F:28])=[O:36].[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH2:25][N:31]3[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]3)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:29])([F:28])[F:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2noc(C3CCCCC3)c2C(F)(F)F)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.015 g, 0.036 mmol) in methanol (2.0 mL) and 1,2-dichloroethane (2.0 mL) was added azetidine-3-carboxylic acid (3.64 mg, 0.036 mmol) followed by 3 drops of acetic acid (2.16 mg, 0.036 mmol). The reaction mixture was heated at 60° C. for 1.5 h. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (4.83 mg, 0.077 mmol) was added. The reaction mixture was then stirred at room temperature for 15 minutes, concentrated under vacuum, and the crude residue was partitioned between dichloromethane and water. The dichloromethane extract was concentrated, and the residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 1-((3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid TFA (0.008 g, 0.016 mmol, 44%) as a white solid. The product had an HPLC ret. time=3.78 min. (condition B). LC/MS M+1=502.07. 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=7.70 Hz), 7.52 (2H, m), 4.41 (2H, s), 4.05-4.34 (4H, m), 3.43-3.62 (1H, m), 2.90-3.21 (4H, m), 2.71 (1H, s), 2.01 (2H, br. s.), 1.76 (4H, br. s.), and 1.28-1.57 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14]O)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][NH:17][CH3:18]>C(O)C.ClCCl>[CH3:16][N:17]([CH3:18])[CH2:14][CH2:13][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 59.6 %

Procedure:
2-(3-Nitro-phenylsulfonyl)-ethanol (0.5 g; 2.6 mmol) was dissolved in 3 mL ethanol and 2 mL of dichloromethane. Then 1 mL of (7.8 mmol) dimethylamine (33% in ethanol) was added, the reaction mixture was subsequently concentrated in vacuo, dissolved in dichloromethane, and the product was precipitated by adding diethyl ether and petrol ether. 0.4 g (1.55 mmol; 59% yield) of dimethyl-[2-(3-nitro-benzenesulfonyl)-ethyl]-amine were obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 69 %

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-[4-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 13, Step B, and was obtained in 69% yield as a cream-colored solid, mp 218°-220° C., homogenous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 576 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6]C(C#N)=[CH:4][N:3]=1.[CH3:10][Mg]Cl.Cl.C([O:16][CH2:17][CH3:18])C>>[C:17]([C:18]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:16])[CH3:10]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[Mg]Cl
Reactant: CCOCC
Agent: Cl
Product: CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
31.91 g (230.3 mmol) of 2-chloro-5-cyano-pyridine are placed in 1.6 liters of diethyl ether under nitrogen, and 155 ml (22% in tetrahydrofuran, 456 mmol) of methylmagnesium chloride are added. The red suspension is stirred for 14 h at RT, poured onto 1.6 liters of ice/water and 320 ml of concentrated hydrochloric acid and stirred for 14 h at RT. Extraction with diethyl ether and methylene chloride, drying with MgSO4 and concentration give 5-acetyl-2-chloro-pyridine; Rf =0.46 (hexane:ethyl acetate=2:1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)[CH3:2].C(O[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41]C(=O)C)[C@@H:33]([O:34]C(=O)C)[C@H:28]([O:29]C(=O)C)[C@H:23]1[O:24]C(=O)C)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:7]1[CH:16]=[CH:17][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[C@@H:22]1[O:39][C@H:38]([CH2:40][OH:41])[C@@H:33]([OH:34])[C@H:28]([OH:29])[C@H:23]1[OH:24]
Reactant: CCSc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCSc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 60.1 %

Procedure:
To a solution of 2-(4-ethylthiobenzyl)phenol (0.51 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (2.4 g) in toluene (6.3 mL) and dichloromethane (2.7 mL) was added boron trifluoride diethyl ether complex (0.78 mL), and the mixture was stirred at room temperature for 9 hours. To the reaction mixture were added ethyl acetate (70 mL) and a saturated aqueous sodium hydrogen carbonate solution (25 mL), and the organic layer was separated. The organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10.5 mL), sodium methoxide (28% methanol solution, 0.08 mL) was added to the solution, and the mixture was stirred at 25° C. for 18 hours. To the reaction mixture were added ethyl acetate (75 mL) and water (20 mL), and the organic layer was separated. The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained colorless solid was washed with diethyl ether and dried under reduced pressure to give 2-(4-ethylthiobenzyl)phenyl β-D-glucopyranoside (0.51 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 101 %

Procedure:
To a solution of ethyl [4-({butyl[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (110 mg, 0.21 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×20 mL) and 2M HCl (20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo affording the title compound as a white solid (103 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:25][CH3:26])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:62]([O:64][C:65]([C:67]1[CH:68]=[C:69]2[N:75]=[C:74](C3C=C4C(=CC=3)N=C(C3C=CC=CC=3Br)C=C4)[N:73]([CH:93]3[CH2:98][CH2:97][CH2:96][CH2:95][CH2:94]3)[C:70]2=[N:71][CH:72]=1)=[O:66])[CH3:63]>CN(C=O)C.CC(O)=O>[CH2:62]([O:64][C:65]([C:67]1[CH:68]=[C:69]2[N:75]=[C:74]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]=[C:12]([C:11]3[C:6]([C:5]5[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:7][CH:8]=[C:9]([O:25][CH3:26])[CH:10]=3)[CH:21]=[CH:20]4)[N:73]([CH:93]3[CH2:98][CH2:97][CH2:96][CH2:95][CH2:94]3)[C:70]2=[N:71][CH:72]=1)=[O:66])[CH3:63]
Reactant: CCOC(=O)c1cnc2c(c1)nc(-c1ccc3nc(-c4ccccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Yield: 40 %

Procedure:
The amine was reacted with Compound 525c (0.314 g, 0.805 mmol) in the presence of HBTU (0.32 g, 0.844 mmol) and DIEA (0.47 mL, 2.68 mmol) in DMF (10 mL), followed cyclization in AcOH (10 mL) according to procedure (2) and (3) in the preparation of Compound 477d. Separation by RP HPLC (from 20% of buffer B to 99% of buffer B) gave the title intermediate (0.19 g, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 3,4-dihydroxybenzoate (10.0 g, 59.4 mmol) in acetone (400 mL) was added potassium carbonate (8.21 g, 59.5 mmol). The mixture was stirred at room temperature (rt) for 30 minutes (min). To the resulting mixture was added benzyl bromide (7 mL, 59.4 mmol) in acetone (200 mL) dropwise over 2 hours (h) and stirring was continued for 48 h. Acetone was removed under vacuum and the resulting residue was partitioned between water (100 mL) and ethyl acetate (3×25 mL). The organic layer was dried over NaSO4, concentrated under vacuum and the resulting crude material purified via column chromatography to afford the product 30 (8.00 g, 52%). 1H NMR (300 MHz, CDCl3): δ 7.70 (m, 2H), 7.50 (m, 5H), 6.95 (m, 1H), 5.70 (s, 1H), 5.10 (s, 2H), 3.93 (s, 3H). MS (M+H): 259.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccn2)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-(2-pyridyl)thiophene-2-carboxylic acid (Maybridge) according to methods A and C; yield 49 mg, 0.14 mmol (66%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=14 Hz, 2H), 2.21 (s, 1H), 2.34 (d, J=14 Hz, 2H), 2.50 (s, 2H), 3.58 (s, 2H), 3.68 (s, 4H), 4.41 (s, 1H), 7.75 (dt, J=7, 6, 1 Hz, 1H), 7.92 (d, J=4 Hz, 1H), 8.00 (d, J=4 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.34 (dt, J=8, 2 Hz, 1H), 8.69 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+; Anal. C21H21F3N2O2.2HCl.0.2H2O.0.1C4H8O2: C, H, N.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)[N:25]=1
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.044 g; 0.187 mmol), 6-(3-fluorobenzyl)picolinic acid (0.045 g; 0.196 mmol), HATU (0.073 g; 0.192 mmol) and N,N-diisopropylethylamine (0.082 mL; 0.466 mmol) in DMF (3 mL) was stirred overnight at room temperature and was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed three times with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% of ethyl acetate in dichloromethane) to give 0.053 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(3-fluorobenzyl)picolinamide as a white solid.